This invention relates to therapeutic peptides useful, e.g., for treatment of benign or malignant proliferation of tissue, for gastrointestinal disorders, and for diabetes.
The amphibian peptide bombesin, pGlu--Gln--Arg--Leu--Gly--Asn--Gln--Trp--Ala--Val--Gly--His--Leu--Met--NH. sub.2 (SEQ ID NO: 1) (Anastasi et al., Experientia 27:166-167 (1971)), is closely related to the mammalian gastrin-releasing peptides (GRP), e.g., the porcine GRP, H.sub.2 N--Ala--Pro--Val--Ser--Val--Gly--Gly--Gly--Thr--Val--Leu--Ala--Lys--Met--T yr--Pro--Arg--Gly--Asn--His--Trp--Ala--Val--Gly--His--Leu--Met--(NH.sub.2) (SEQ ID NO: 2) (McDonald et al., Biochem. Biophys. Res. Commun. 90:227-233 (1979)) and human GRP, H.sub.2 N--Val--Pro--Leu--Pro--Ala--Gly--Gly--Gly--Thr--Val--Leu--Thr--Lys--Met--T yr--Pro--Arg--Gly--Asn--His--Trp--Ala--Val--Gly--His--Leu--Met (NH.sub.2)(SEQ ID NO: 3). Bombesin has been found to be a growth factor for a number of human cancer cell lines, including small-cell lung carcinoma (SCLC), and has been detected in human breast and prostate cancer (Haveman et al., eds. Recent Results in Cancer Research--Peptide Hormones in Lung Cancer, Springer-Verlag, New York:1986). A number of these cancers are known to secrete peptide hormones related to GRP or bombesin. Consequently, antagonists to bombesin have been proposed as agents for the treatment of these cancers.
Cuttitta et al. demonstrated that a specific monoclonal antibody to bombesin inhibited in vivo the growth of a human small-cell lung cancer cell line xenografted to nude mice (Cuttitta et al., Cancer Survey 4:707-727 (1985)). In 3T3 murine fibroblasts which are responsive to the mitotic effect of bombesin, Zachary and Rozengurt observed that a substance P antagonist (Spantide) acted as a bombesin antagonist (Zachary et al., Proc. Natl. Acad. Sci. (USA), 82:7616-7620 (1985)). Heinz-Erian et al. replaced His at position 12 in bombesin with D--Phe and observed bombesin antagonist activity in dispersed acini from guinea pig pancreas (Heinz-Erian et al., Am. J. of Physiol. 252:G439-G442 (1987)). Rivier reported work directed toward restricting the conformational freedom of the bioactive C-terminal decapeptide of bombesin by incorporating intramolecular disulfide bridges; however, Rivier mentioned that, so far, bombesin analogs with this modification fail to exhibit any antagonist activity (Rivier et al., "Competitive Antagonists of Peptide Hormones," in Abstracts of the International Symposium on Bombesin-Like Peptides in Health and Disease, Rome, Italy (October, 1987).
Abbreviations (uncommon): ##STR1## Pal=3-pyridyl-alanine .beta.-leu=.beta.-homoleucine
.gamma.-leu=gamma-homoleucine PA1 D-Cpa=D-p-chlorophenylalanine PA1 HyPro=hydroxyproline PA1 Nal=naphthylalanine PA1 Sar=sarcosine PA1 F.sub.5 -Phe=penta-fluoro-Phenylalanine PA1 Sta (statine)=(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid, and has the chemical structure: ##STR2## AHPPA=(3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid, and has the chemical structure: ##STR3## ACHPA=(3S, 4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid and has the chemical structure: ##STR4## R=right (D) configuration; S=left (L) configuration; PA1 racemate=equal mix of R and S PA1 1-methyl-His; PA1 3-methyl-His=methyl (CH.sub.3) group on nitrogen at positions 1 or 3 of Histidine: ##STR5## PA1 A.sup.1 =the D or L-isomer of any of pGlu, Nle, .alpha.-aminobutyric acid, or the D-isomer of any of Ala, Val, Gln, Asn, Leu, Ile, Met, p--X--Phe (where X=F, Cl, Br, NO.sub.2, OH, H or CH.sub.3), F.sub.5 --Phe, Trp, Cys, or .beta.-Nal, or is deleted; PA1 A.sup.2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X--Phe (where X=F, Cl, Br, NO.sub.2, OH, H or CH.sub.3), Trp, Cys, .beta.-Nal, His, 1-methyl-His, or 3-methyl-His; PA1 A.sup.4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, .alpha.-aminobutyric acid, Met, p-X--Phe (where X=F, Cl, Br, NO.sub.2, OH, H or CH.sub.3), Trp, Cys, or .beta.-Nal; PA1 A.sup.5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, .alpha.-aminobutyric acid, Met, Val, p-X--Phe (where X=F, Cl, Br, OH, H or CH.sub.3), Trp, Thr, or .beta.-Nal; PA1 A.sup.6 =Sar, Gly, or the D-isomer of any of Ala, N-methyl-Ala, Val, Gln, Asn, Leu, Ile, Met, p-X--Phe (where X=F, Cl, Br, NO.sub.2, OH, H or CH.sub.3), Trp, Cys, or .beta.-Nal; PA1 A.sup.7 =1-methyl-His, 3-methyl-His, or His; PA1 A.sup.0 =Gly, D-Phe, or is deleted; PA1 A.sup.1 =p-Glu, D-Phe, D-Ala, D-.beta.-Nal, D-Cpa, or D-Asn; PA1 A.sup.2 =Gln, His, 1-methyl-His, or 3-methyl-His; PA1 A.sup.4 =Ala; PA1 A.sup.5 =Val; PA1 A.sup.6 =Sar, Gly, D-Phe, or D-Ala; PA1 A.sup.7 =His; and PA1 and, where W is (I) and R.sub.3 is CH.sub.2 or CH.sub.2 --CH.sub.2, Z.sub.1 is the identifying group of Leu or Phe, where W is (I) and R.sub.3 is CHOH--CH.sub.2, Z.sub.1 is the identifying group of Leu, cyclohexyl-Ala, or Phe and each R.sub.5 and R.sub.6 is H, and where W is (I), V is NHR.sub.6, and R.sub.6 is NH.sub.2 ; where W is (II) and R.sub.4 is CH.sub.2 --NH each Z.sub.1 is the identifying group of Leu, or Phe, and Z.sub.2 is the identifying group of Leu or Phe; where W is (III), Z.sub.1 is the identifying group of any one of the amino acids Leu or p-X--Phe (where X=H, F, Cl, Br, NO.sub.2, OH or CH.sub.3); and each Z.sub.2, Z.sub.3 and Z.sub.4, independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; and where W is (IV), each Z.sub.20 and Z.sub.30, is H; and each R.sub.1 and R.sub.2, independently, is H, lower alkyl, or lower acyl. PA1 D-.beta.-Nal--Gln--Trp--Ala--Val--Gly--His--Leu.PSI.CH.sub.2 NH!Phe--NH.sub.2, PA1 D-Phe--Gln--Trp--Ala--Val--Gly--His--Leu--ethylamide, PA1 p-Glu--Gln--Trp--Ala--Val--Gly--His--statine-amide, (SEQ ID NO: 4) PA1 D-Phe--Gln--Trp--Ala--Val--Gly--His--Leu.PSI.CH.sub.2 NH!-D-Phe--NH.sub.2, PA1 D-Cpa--Gln--Trp--Ala--Val--Gly--His-.beta.-Leu--NH.sub.2, PA1 D-Cpa--Gln--Trp--Ala--Val--D--Ala--His-.beta.-Leu--NH.sub.2, PA1 D-Cpa--Gln--Trp--Ala--Val--Gly--His--Leu.PSI.CH.sub.2 NH!--Phe--NH.sub.2. PA1 D-Phe--Gln--Trp--Ala--Val--N-methyl-D-Ala--His--Leu-methylester, PA1 D-F.sub.5 --Phe--Gln--Trp--Ala--Val--D--Ala--His--Leu-methylester, PA1 D-F.sub.5 --Phe--Gln--Trp--Ala--Val--D--Ala--His--Phe-methylester, PA1 D-F.sub.5 --Phe--Gln--Trp--Ala--Val--Gly--His--Phe-methylester, and PA1 D-F.sub.5 --Phe--Gln--Trp--Ala--Val--Gly--His--Leu-methylester. PA1 Tyr--Ala.sup.2 --Asp--Ala--Ile--Phe--Thr--Asn--Ser.PSI.CH.sub.2 NH!Tyr--Arg--Lys--Val--Leu--Gly--Gln--Leu--Ser--Ala--Arg--Lys--Leu--Leu--G ln--Asp--Ile--Met--Ser--Arg--NH.sub.2 ; (SEQ ID NO: 5); most preferably, the peptide contains, D-Ala, N-methyl-D-Ala, or a-aminobutyric acid in position 2. (Non-peptide bonds in which the peptide bond is reduced are symbolized herein by ".PSI.CH.sub.2 NH!" or ".PSI.".) PA1 A.sup.1 --Gln--Trp--Ala--Val--A.sup.6 --His--A.sup.8 --O--R,